In this section of the NCDDG, we will continue pre-clinical studies of anti-Tf receptor antibodies as therapy for cancer. Substantial progress has been made in implementing the original goals of the NCDDG with respect to anti-Tf receptor antibodies. A Phase Ia trial of anti-Tf receptor 42/6 has been completed, and a trial of 2 IgG anti-Tf receptor antibodies (A27.15 and E2.3) is pending large animal toxicology. Because these IgG antibodies are being developed for clinical trials, they will be used in future in vitro and in vivo experimental studies in this program. To extend the effectiveness and range of activity of these antibodies, exploratory studies have been performed combining them with anti-lL6 receptor antibodies and chemicals which inhibit receptor display or signal transduction. Each set of studies performed and planned is based on a rationale demonstrating ability to overcome antigeneic heterogeneity or to modify receptor target function. These studies will include in vitro and in vivo investigation of anti-Tf receptor antibodies used in concert with a novel preparation of the Fe chelator desferral and modulation of Tf receptor function by retinoids. In vivo studies in this program will be closely coordinated with those in Project B, which will test these potential therapies in a murine system in which toxicity can be assessed. In this program, new therapies will be tested in SCID mice to demonstrate the in vivo activity of achievable concentrations against human cells. Finally, a discovery program will be conducted in collaboration with lmmunex, Inc., Using a novel flow cytometry assay to specifically identify new anti-receptor antibodies directly mediating programmed cell death (apoptosis) of solid tumor cells.